KR20090021167A - Oral composition comprising 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid or salt thereof - Google Patents

Abstract

An oral composition comprising 3-[5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl]propionic acid or a salt thereof and polyvinylpyrrolidone. The oral composition is useful as a pharmaceutical composition for oral application having the following properties (1) to (3): (1) no new-type facility is required for the production of the composition; (2) the composition can be produced by a simple process; and (3) the composition can be dissolved stably in the gastrointestinal tract even when the pH value in the gastrointestinal tract varies and therefore is improved in gastrointestinal adsorption.

Description

3- ｛5- [4- (cyclopentyloxy) -2-hydroxybenzoyl] -2-[(3-hydroxy-1,2-benzisoxazol-6-yl) methoxy] phenyl] propionic acid or its ORAL COMPOSITION COMPRISING 3- ｛5- [4- (CYCLOPENTYLOXY) -2-HYDROXYBENZOYL] -2-[(3-HYDROXY-1,2-BENZISOXAZOL-6-YL) METHOXY] PHENYL｝ PROPIONIC ACID OR SALT THEREOF}

The present invention provides 3- {5- [4- (cyclopentyloxy) -2-hydroxybenzoyl] -2-[(3-hydroxy-1,2-benzisoxazol-6-yl) methoxy] phenyl The present invention relates to an oral composition comprising propionic acid or a salt thereof and polyvinylpyrrolidone.

3- {5- [4- (cyclopentyloxy) -2-hydroxybenzoyl] -2-[(3-hydroxy-1,2-benzisoxazol-6-yl) methoxy] phenyl} propionic acid (hereinafter Or a salt thereof is a compound under development as a therapeutic agent for inflammatory diseases targeting the transcription factor AP-1 (Patent Document 1).

T-5224 is a poorly soluble drug with low solubility in liquid (acid to neutral region) in the summon tube. Therefore, when orally administered solid T-5224, absorption from the digestive tract is not sufficient. In addition, when the basic solution of T-5224 is orally administered, T-5224 precipitates due to the change of the liquid in the digestive tract, and thus sufficient absorption is not achieved.

Various manufacturing techniques have been examined for improving the solubility of poorly soluble drugs. For example, (1) a method of improving solubility by using a poorly soluble drug as a salt, (2) a method of amorphousization, (3) a method of solubilizing by entrapment with cyclodextrin, (4) surfactant And solubilization by adding (5) a method of dissolving in a solvent (eg, macrogol and propylene glycol, etc.) having affinity with poorly soluble drugs, and (6) a method of atomizing. (Non-Patent Document 1)

However, (1) the salt of T-5224 precipitates due to the change in liquidity in the digestive tract. (2) The method of solubilizing by adding a surfactant may damage the digestive tract by the surfactant. (3) The method of amorphous, the method of clathrate with cyclodextrin, and the method of micronization require a special manufacturing equipment, a complicated process, and are not easy to manufacture. (4) Familiar with poorly soluble drugs. The method of dissolving in a chemical solvent may cause side effects due to the solvent, and requires a special manufacturing equipment and a complicated process such as soft gelatinization, and is not easy to manufacture.

Formulations containing T-5224 or its salts, which have good absorption upon oral administration and can be prepared simply, are not yet known.

Patent Document 1: International Publication No. 03/042150 Pamphlet

[Non-Patent Document 1] Powder and Powder Society, Formulation and Particle Design Society, `` Particle Design and Processing Technology, '' First Edition, Jiho, September 1, 2003, p.205-211

(1) It does not require any new manufacturing equipment, (2) It is manufactured by a simple process, and (3) It is used orally for maintaining stable dissolution even by changing pH in the digestive tract and improving the absorption of the digestive tract. Compositions are desired.

Under such circumstances, the present inventors have intensively studied and found that the oral composition in which polyvinylpyrrolidone is added to T-5224 greatly improves the absorption of T-5224 even in the neutral solubility neutral region. It was. In particular, an oral solid composition containing a basic substance and a polyvinylpyrrolidone added with a 5W / V% aqueous solution having a pH of 10 or higher in T-5224, and an aqueous oral liquid solution containing polyvinylpyrrolidone added to T-5224, It has been found to greatly improve the absorption of T-5224 and has come to complete the present invention.

The T-5224 oral composition containing the polyvinylpyrrolidone of the present invention is prepared by (1) no new manufacturing equipment, (2) prepared by a simple process, and (3) pH in the digestive tract. It is also useful as an oral pharmaceutical composition that maintains dissolution stably even by the change of and improves the absorption of the digestive tract.

EMBODIMENT OF THE INVENTION Below, this invention is demonstrated in detail.

% Used in this specification means weight% unless there is particular notice, and W / V% means the weight / vol% in 20 degreeC. pH means the value in 20 degreeC.

The pharmaceutical composition of the present invention is an oral composition comprising T-5224 or a salt thereof and polyvinylpyrrolidone (PVP).

More specifically, oral solid composition and T-5224 or a salt thereof, characterized in that T-5224 or a salt thereof, polyvinylpyrrolidone and a 5W / V% aqueous solution contains a basic substance exhibiting a pH of 10 or more and An aqueous oral liquid formulation containing polyvinylpyrrolidone.

The oral solid composition of the present invention improves and maintains solubility in the neutral region of poorly soluble T-5224 as compared with a pharmaceutical composition containing no polyvinylpyrrolidone and a basic substance, and greatly improves water absorption.

T-5224 or its salt used for this invention can be manufactured by the method as described in the international publication 03/042150 pamphlet, for example.

The amount of T-5224 contained in the oral solid composition of the present invention is 0.1 to 50% with respect to the composition, preferably 1 to 30%.

In the case of T-5224 or a salt thereof, when isomers (for example, geometric isomers and tautomers) exist, the present invention includes these isomers, and includes solvates, hydrates, and crystals of various shapes. It is.

As a "basic substance whose 5 W / V% aqueous solution shows pH10 or more", sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, meglumine, arginine, arginine hydrate, salts, etc. are mentioned, for example. Preferably, L-arginine, its hydrate, and potassium carbonate are mentioned, More preferably, L-arginine and its hydrate are mentioned.

The substance which has optical isomers, such as arginine, may be optical isomers, such as L body and D body, their mixture, and those hydrates.

The compounding quantity of a basic substance may be 0.1-30 weight part with respect to T-5224, Preferably it may be 0.5-10 weight part. More preferably, 1-6 weight part is good.

The polyvinylpyrrolidone used in the oral solid composition of the present invention is not particularly limited, but for example, polyvinylpyrrolidone K-30, polyvinylpyrrolidone K-25 and polyvinylpyrrolidone K- 17 and the like.

The compounding quantity of polyvinylpyrrolidone should just be 0.1-30 weight part with respect to T-5224, Preferably it should be 0.1-6 weight part. More preferably, it is good in it being 0.3-3 weight part.

In the solid composition for oral use of the present invention, an excipient can be further added.

As an excipient, For example, Sugar alcohols, such as erythritol, mannitol, xylitol, and sorbitol; Sugars such as white sugar, minute sugar, lactose and glucose; cyclodextrins such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl β-cyclodextrin and sodium sulfobutyl ether β-cyclodextrin; Celluloses such as crystalline cellulose and microcrystalline cellulose; And starch such as corn starch, potato starch and alpha starch. You may add these excipients 1 type or in combination of 2 or more types. Preferred excipients include water-soluble excipients such as sugar alcohols, sugars and cyclodextrins. As sugar alcohols, mannitol, sugars are lactose, and cyclodextrins are more preferably β-cyclodextrin and hydroxypropyl β-cyclodextrin.

The addition amount of an excipient is not specifically limited, What is necessary is just to add the quantity suitable for a formulation.

In the solid composition for oral use of this invention, the additive used for a chemical | medical agent can be used normally within the range which does not impair the effect of this invention. As such an additive, a disintegrating agent, a binder, a lubricant, a mating agent, a coloring agent, a flavoring agent, surfactant, a coating agent, a plasticizer, etc. are mentioned.

Examples of the disintegrating agent include carmellose, carmellose calcium, croscarmellose sodium, carboxymethyl starch sodium, crospovidone, low-substituted hydroxypropyl cellulose, partially α-starched starch, and the like.

Examples of the binder include hydroxypropyl cellulose, sodium camelos, methyl cellulose and the like.

Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, talc, hydrous silicon dioxide, hard silicic anhydride, and sucrose fatty acid ester.

As mating agents, for example, aspartame, saccharin, stevia, thaumatin, acesulfame Potassium and the like can be given.

Examples of the coloring agent include titanium dioxide, iron trioxide, yellow iron trioxide, black iron oxide, edible red No. 102, edible yellow No. 4, and edible yellow No. 5 and the like.

As a flavoring agent, For example, essential oils, such as orange oil, lemon oil, peppermint oil, and pine oil; Essences such as orange essence and peppermint essence; Flavors such as cherry flavor, vanilla flavor and fruit flavor; Powdered flavors such as apple micron, banana micron, pitch micron, strawberry micron and orange micron; vanillin; And ethyl vanillin.

Examples of the surfactant include sodium lauryl sulfate, sodium dioctyl sulfate, polysorbate and polyoxyethylene hydrogenated castor oil.

As the coating agent, for example, hydroxypropylmethyl cellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, ethyl cellulose, cellulose acetate cellulose, hydroxymethyl cellulose phthalate, methacrylic acid copolymer L And methacrylic acid copolymer LD, methacrylic acid copolymer S and the like.

As a plasticizer, triethyl citrate, macrogol, triacetin, propylene glycol, etc. are mentioned, for example.

These additives may be used in any one kind or in combination of two or more kinds, and the blending amount is not particularly limited, and may be appropriately blended so that the effect is sufficiently expressed according to each purpose.

The oral solid composition of the present invention is a tablet, capsule, granules, granules, fine powder, powder, fast disintegrating tablets, dissolvable preparations, dry syrups, using appropriately formulated preparations such as pharmaceutically acceptable excipients, carriers and diluents. Or as preparations such as powder preparations. In the composition of the present invention, in order to dissolve T-5224 which is a poorly water-soluble substance in the digestive tract and to maintain the state, it is preferable to keep the composition T-5224, the basic substance and polyvinylpyrrolidone in close contact. For example, tablets, capsules, and granules (granules, fine granules, powders, fast disintegrating tablets, dissolving agents in use, dry syrups or powders, etc.) are preferable. More preferably, tablets and capsules can be mentioned. More preferably, tablets can be mentioned.

The method of administration, dosage and frequency of administration can be appropriately selected depending on the age, weight and symptoms of the patient, but in general, the amount of the drug that can be used can be administered once a day, once or several times. For adults, T-5224 may be administered by dividing 1 to 2000 mg once to several times per day.

The formulation of the oral solid composition of the present invention is not particularly limited and may be carried out by a conventional method. For example, in the case of tablets, a composition such as a tableting method and a direct tableting method after producing a granulated product by fluidized bed granulation, wet crushing granulation, stirring granulation, dry granulation and extrusion granulation The method of mixing and tableting directly is mentioned. In the case of a capsule, the method of filling a granulated material or a composition as it is is mentioned. The oral solid composition of the present invention may be used after being pulverized as necessary.

In the case of producing a tablet, a direct tableting method is preferable, and a direct tableting method using a water-soluble direct tableting excipient is more preferable. Examples of the water-soluble direct tableting excipients include direct tableting lactose, direct tableting mannitol, and direct tableting sorbitol.

As an excipient for direct tableting, it is preferable to use mannitol for direct tableting.

When a 5W / V% aqueous solution is prepared by direct tableting using L-arginine as a basic substance having a pH of 10 or more, it is preferable to tablet by using a L-arginine hydrate or a humidified product of L-arginine and then dry it. Do. In addition, a humidified product of L-arginine hydrate or L-arginine; And it is more preferable to compress using a humidified product of polyvinylpyrrolidone, and then to dry. By tableting using a humidified product of L-arginine hydrate or L-arginine, physical stability such as hardness of tablets is improved.

The oral aqueous solution of the present invention is significantly improved in dissolution retention effects and stability against changes in pH compared to oral aqueous solutions containing solubilizers or dissolution aids such as hydroxypropylmethylcellulose and polyethylene glycol 6000. In addition, the water absorption of T-5224 was greatly improved.

T-5224 or its salt used for the oral aqueous liquid preparation of this invention can be manufactured, for example by the method of the international publication 03/042150 pamphlet.

The amount of T-5224 contained in the aqueous oral solution of the present invention is 0.001 to 50 W / V%, preferably 0.01 to 20 W / V% of the aqueous oral solution.

In the case of T-5224 or a salt thereof, when isomers (for example, geometric isomers and tautomers) exist, the present invention includes these isomers, and includes solvates, hydrates, and crystals of various shapes. It is.

The polyvinylpyrrolidone used in the aqueous oral liquid preparation of the present invention is not particularly limited, but for example, polyvinylpyrrolidone K-30, polyvinylpyrrolidone K-25 and polyvinylpyrrolidone K- 17 and the like. The compounding quantity of polyvinylpyrrolidone should just be 0.1-100 weight part with respect to T-5224 or its salt, Preferably it should be 0.5-20 weight part. More preferably, it is good in it being 1-10 weight part.

The oral aqueous liquid preparation of the present invention is not particularly limited and may be formulated by a conventional method. For example, T-5224 or its salt and polyvinylpyrrolidone are dissolved in an aqueous solvent. Preferably, the basic material is dissolved in an aqueous solvent in which it is dissolved. As a basic substance, potassium hydroxide, sodium hydroxide, magnesium hydroxide, sodium hydrogencarbonate, sodium lactate, sodium citrate, L-arginine, etc. are mentioned, for example.

Moreover, the obtained aqueous liquid agent can adjust pH with a pH adjuster etc. as needed.

It is preferable that it is pH1-10, and, as for the oral aqueous liquid agent of this invention, it is more preferable that it is pH3-9.

The oral aqueous liquid preparation of this invention can use the additive normally used for a chemical | medical agent within the range which does not impair the effect of this invention. As such an additive, a pH adjuster, a copper, a flavoring agent, surfactant, a dissolving agent, etc. are mentioned.

As a pH adjuster, hydrochloric acid, citric acid, glycine, succinic acid, acetic acid, tartaric acid, lactic acid, maleic acid, etc. are mentioned, for example.

As mating agents, for example, aspartame, saccharin, stevia, tomate and acesulfame potassium may be mentioned.

As a flavoring agent, For example, essential oils, such as orange oil, lemon oil, peppermint oil, and pine oil; Essences such as orange essence and peppermint essence; Flavors such as cherry flavor, vanilla flavor and fruit flavor; Powdered flavors such as apple micron, banana micron, pitch micron, strawberry micron and orange micron; vanillin; And ethyl vanillin.

Examples of the surfactant include sodium lauryl sulfate, sodium dioctyl sulfate, polysorbate and polyoxyethylene hydrogenated castor oil.

As a solubilizer, purified water, ethanol, propylene glycol, polyethylene glycol, glycerin, etc. are mentioned.

These additives may be used in any one kind or in combination of two or more kinds, and the blending amount is not particularly limited, and may be suitably blended so as to sufficiently express the effect in accordance with each purpose.

The aqueous oral liquid preparation of the present invention can be used as a preparation such as a liquid preparation, a syrup preparation, a lemonade preparation, and the like, using a preparation preparation such as a pharmaceutically acceptable excipient, carrier, and diluent as appropriate. In addition, the administration method, dosage and frequency of administration can be appropriately selected depending on the age, weight and symptoms of the patient, but in general, it is good to divide and administer an amount that can exert the drug once a day, once or several times, Usually, T-5224 should be administered to adults by dividing 1 to 2000 mg once to several times.

Next, the usefulness of this invention is demonstrated through the following test example.

Test Example 1. Dissolution test (solid composition for oral use)

The composition of Example 1 and the composition of Comparative Examples 1-3 were used for the sample. All are tablets containing 10 mg of T-5224.

The test by the Japanese Pharmacy Dissolution Test Paddle Method was performed. The rotation speed of the paddle was 50 rpm. The sample was put into 250 mL of the Japanese Pharmacopoeia Disintegration Test No. 1 solution, and stirred for 30 minutes (test solution pH 1.2). After 30 minutes, 125 mL of 0.2 mol / L disodium hydrogen phosphate was added (test solution pH5.6), and after another 30 minutes, 125 mL (test solution pH6.8) was added to change the pH over time. The test solution was collected over time, and the dissolution rate (%) of T-5224 was determined by the absorbance method. The results are shown in Table 1.

The tablet of Example 1 containing T-5224, polyvinylpyrrolidone and L-arginine, contains the tablet of Comparative Example 1 containing no polyvinylpyrrolidone and L-arginine, polyvinylpyrrolidone It showed better elution in the acid and neutral test solution than the tablet of Comparative Example 2 containing no L-arginine and the tablet of Comparative Example 3 containing L-arginine and no polyvinylpyrrolidone.

Experimental Example 2. Dissolution test (solid composition for oral use)

The composition of Example 2, the composition of Example 3, and the composition of Comparative Examples 4-7 were used for the sample. All are tablets containing 10 mg of T-5224.

The same pH variation dissolution test as in Experiment 1 was carried out. The results are shown in Table 2.

The composition of Example 2 to which L-arginine was added as a basic substance, and the composition of Example 3 to which potassium carbonate was added, the composition of Comparative Example 4 in which the 5W / V% aqueous solution added sodium hydrogencarbonate which is a basic substance below pH10. , The composition of Comparative Example 5 added with glycine, a weakly acidic water-soluble additive, the composition of Comparative Examples 6 and 7 added with anhydrous calcium hydrogen phosphate and magnesium metasilicate aluminate of a basic substance insoluble in water. It was.

Experimental Example 3. Dissolution test (solid composition for oral use)

As the samples, the compositions of Examples 8 to 11, Comparative Example 9, and Comparative Example 10 were used. All are tablets or capsules containing 10 mg of T-5224.

The test by the Japanese Pharmacy Dissolution Test Paddle Method was performed. The rotation speed of the paddle was 50 rpm. The sample was put into 900 mL McIlvaine buffer of pH6.8, and it stirred for 30 minutes. The test solution was collected over time, and the dissolution rate (%) of T-5224 was determined by the absorbance method. McIlvaine buffer of pH6.8 was adjusted to pH6.8 using 0.1 mol / L citric acid and 0.2 mol / L disodium hydrogen phosphate. The results are shown in Table 3.

Compared with the composition of Comparative Example 9 in which L-arginine was added three times by weight to T-5224 and no polyvinylpyrrolidone was added, and the composition of Comparative Example 10 in which T-5224 was filled into a capsule, The compositions in which 0.3 times (Example 11), 0.5 times (Example 8), 1 times (Example 9), and 3 times (Example 10) were added to the weight ratio of lollidon showed good elution.

Test Example 4. Dissolution test (solid composition for oral use)

The composition of Examples 17 and 18 was used for the sample. All are capsules containing 20 mg of T-5224.

The test by the Japanese Pharmacy Dissolution Test Paddle Method was performed. The rotation speed of the paddle was 50 rpm. The sample was put into 900 mL of the buffer adjusted to pH6.8 using 0.025 mol / L citric acid and 0.05 mol / L disodium hydrogen phosphate, and stirred for 30 minutes. The test solution was collected over time, and the dissolution rate (%) of T-5224 was determined by the absorbance method. The results are shown in Table 4.

The composition of Example 17 to which mannitol for direct acting was added and the composition of Example 18 to which added corn starch as an excipient showed good elution property.

Experimental Example 5. Dissolution test (solid composition for oral use)

As the sample, the compositions of Examples 19, 20, and 22 were used. Capsules containing 80 mg and 40 mg of T-5224 and tablets containing 40 mg of T-5224.

The same dissolution test as in Experiment 4 was carried out. The results are shown in Table 5.

Both the tablet of Example 22 containing 40 mg of T-5224 and the capsule of Example 20 and the capsule of Example 19 containing 80 mg of T-5224 showed good elution.

Test Example 6 Oral Administration of Dogs (Oral Solid Composition)

As the sample, the compositions of Examples 4 to 10 and Comparative Example 8 were used.

A male beagle dog (n = 4-6 dogs) weighing 10-15 kg was fasted for about 17 hours from the day before administration, and in the samples of Examples 4-10, 10 mg / kg of T-5224 was sampled in Comparative Example 8 Eosin was administered orally with T-5224 30 mg / kg. After administration, 20 mL of water was taken. Blood was collected from the cell (forelimb) vein over time, and the obtained plasma was subjected to acetonitrile and subjected to protein-treatment. Then, the concentration of T-5224 was measured by LC-MS / MS method, and the concentration-hour in plasma was 0 to 6 hours. The area (AUC) value under the curve was calculated | required. The unit of AUC value is µg / hr / mL. The results are shown in Table 6.

Compared with Comparative Example 8 in which 30 mg / kg was orally administered as a dosage, the AUC value of the oral solid composition (Examples 4 to 10) of the present invention orally administered 10 mg / kg was greatly improved.

Test Example 7. Solubility in neutral (oral aqueous solution)

The composition of Examples 27-29 and the composition of Comparative Examples 11-13 were used for the sample. All are liquid solutions containing 10 mg / mL of T-5224.

Each sample was diluted with a pH6.8 buffer (adjusted with 0.1 mol / L citric acid and 0.2 mol / L disodium hydrogen phosphate) so that the concentration of T-5224 was about 100 μg / mL. The solution was left to stand in a 37 ° C. water bath, centrifuged after 1 hour, and the concentration of T-5224 (µg / mL) in the supernatant was measured by high performance liquid chromatography. The results are shown in Table 7.

The liquid preparations of Examples 27 to 29 containing polyvinylpyrrolidone with respect to the liquid preparation of Comparative Example 11 containing no additives, Comparative Example 12 containing hydroxypropylmethylcellulose and Comparative Example 13 containing macrogol 6000 All showed good solubility maintenance even when diluted with pH6.8 buffer.

Test Example 8 Dissolution Test (Aqueous liquid solution for oral use)

The composition of Examples 30-35 and the composition of Comparative Examples 14-15 were used for the sample.

The test by the Japanese Pharmacy Dissolution Test Paddle Method was performed. The rotation speed of the paddle was 50 rpm. A sample containing 10 mg of T-5224 was added to 250 mL of the Japanese Pharmacopoeia Disintegration Test No. 1 solution, and stirred for 30 minutes (test solution pH1.2). After 30 minutes, 125 mL of 0.2 mol / L disodium hydrogen phosphate was added (test solution pH5.6), and after another 30 minutes, 125 mL (test solution pH6.8) was added to change the pH over time. The test solution was collected over time, and the dissolution rate (%) of T-5224 was determined by the absorbance method. The results are shown in Table 8.

Example 30, 31, 33, 34 which is the acidic aqueous solution containing polyvinylpyrrolidone, and the basic aqueous solution containing polyvinylpyrrolidone compared with the comparative example 14 suspended with water, and the comparative example 15 which is a basic aqueous solution. Examples 32 and 35 all showed good dissolution holding properties.

Test Example 9 Oral Administration of Dogs (Oral Aqueous Solution)

As the sample, the compositions of Examples 36 and 37 and Comparative Example 16 were used.

Male beagle dogs (4-5) weighing 10-15 kg are fasted for about 17 hours from the day before administration, and in the samples of Examples 36 and 37, 10 mg / kg of T-5224 is used in the samples of Comparative Example 16, T-5224 30 mg / kg was administered orally. After administration, 20 mL of water was taken. Blood was collected from the vein over time, and the obtained plasma was deproteinized with acetonitrile. Then, the concentration of T-5224 was measured by LC-MS / MS, and the plasma concentration-time curve area under 0-6 hours. The (AUC) value was obtained. The unit of AUC value is µg / hr / mL. The results are shown in Table 9.

Compared with Comparative Example 16 in which 30 mg / kg was orally administered as a dose, the AUC value of the oral solid composition (Examples 36 and 37) of the present invention orally administered 10 mg / kg was greatly improved.

Next, the present invention will be described with reference to Examples and Comparative Examples, but the present invention is not limited thereto. In addition, in the Example and the comparative example of an oral solid composition, both T-5224 and L-arginine were used by grinding.

Comparative Example 1

150 mg of T-5224, lactose for tablets (Tabletose 80, manufactured by Meggle Corp.), 2400 mg of crospovidone (Kollidon CL, manufactured by BASF Corp.) and 22.5 mg of magnesium stearate were weighed and mixed, After filtering, the mixture was mixed to obtain a tableting powder. Tableting powder 175 mg was compressed into a mortar having a diameter of 8.0 mm to obtain a tablet containing 10 mg of T-5224.

Comparative Example 2

T-5224 150 mg, polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP) 450 mg, direct lactose (Tabletose 80, manufactured by Meggle Corp.) 1950 mg, crospovidone (Kollidon CL, BASF Corp 52.5 mg and 22.5 mg of magnesium stearate were weighed out, mixed, filtered through a 30 mesh sieve, and mixed to obtain a tableting powder. Tableting powder 175 mg was compressed into a mortar having a diameter of 8.0 mm to obtain a tablet containing 10 mg of T-5224.

Comparative Example 3

T-5224 150 mg, L-arginine (manufactured by Ajinomoto Corp.) 450 mg, direct lactose (Tabletose 80, manufactured by Meggle Corp.) 1950 mg, crospovidone (Kollidon CL, manufactured by BASF Corp.) 52.5 mg, magnesium stearate 22.5 MG was weighed, mixed, filtered through a 30 mesh sieve, and mixed to obtain a tableting powder. Tableting powder 175 mg was compressed into a mortar having a diameter of 8.0 mm to obtain a tablet containing 10 mg of T-5224.

Comparative Example 4

100 mg of T-5224, polyvinylpyrrolidone K-30 (Plasdone K29 / 32, manufactured by ISP) 300 mg, sodium bicarbonate 1000 mg, β-cyclodextrin (Celldex B-100, Nihon Shokuhin kako Corp. Ltd. 1) 1000 mg, 50 mg of crospovidone (Kollidon CL, BASF Corp.), 25 mg of magnesium stearate were weighed, mixed, sieved through a 30 mesh sieve, and mixed to form a tableting powder. The tableting powder 247.5 mg was compressed into a mortar with a diameter of 8.5 mm to obtain a tablet containing 10 mg of T-5224.

Comparative Example 5

100 mg of T-5224, polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP) 300 mg, glycine 600 mg, β-cyclodextrin (Celldex B-100, manufactured by Nihon Shokuhin kako Corp. Ltd.) 1000 mg, 40 mg of crospovidone (Kollidon CL, manufactured by BASF Corp.) and 20 mg of magnesium stearate were weighed, mixed, sieved through a 30 mesh sieve, and mixed to form a tableting powder. Tableting powder 206 mg was compressed into a mortar with a diameter of 8.5 mm to obtain a tablet containing 10 mg of T-5224.

Comparative Example 6

100 mg of T-5224, polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) 300 mg, anhydrous calcium hydrogen phosphate (Fujicalin SG, Fuji Kagaku) 600 mg, β-cyclodextrin (Celldex B- 100, Nihon Shokuhin kako Corp. Ltd.) 1000 mg, crospovidone (Kollidon CL, BASF Corp.) 40 mg, magnesium stearate 20 mg were weighed, mixed, sieved through a 30 mesh sieve, mixed and tableted It was made into powder. Tableting powder 206 mg was compressed into a mortar with a diameter of 8.5 mm to obtain a tablet containing 10 mg of T-5224.

Comparative Example 7

T-5224 100 mg, polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) 300 mg, magnesium metasilicate aluminate (Neusilin VS2, manufactured by Fuji Kagaku) 600 mg, β-cyclodextrin (Celldex B -100, Nihon Shokuhin kako Corp. Ltd. 1000 mg, crospovidone (Kollidon CL, BASF Corp.) 40 mg, magnesium stearate 20 mg were weighed, mixed, sieved through a 30 mesh sieve, and then mixed, It was made into a tableting powder. Tableting powder 206 mg was compressed into a mortar with a diameter of 8.5 mm to obtain a tablet containing 10 mg of T-5224.

Comparative Example 8

T-5224 was sieved through a 60 mesh sieve, and 450 mg was filled into 000 capsules to obtain a capsule containing 450 mg of T-5224.

Comparative Example 9

100 mg of T-5224, 300 mg of L-arginine (manufactured by Ajinomoto Corp.), mannitol (Parteck M100, manufactured by Merck Corp.) 910 mg, sodium carboxymethyl starch (Primogel, manufactured by Matsutani Corp.) 27 mg, stearic acid Magnesium 14 mg was weighed, mixed, filtered through a 30 mesh sieve, and mixed to obtain a tableting powder. 135 mg of tableting powder was compressed into a mortar with a diameter of 7 mm to obtain a tablet containing 10 mg of T-5224.

Comparative Example 10

10 mg of T-5224 was filled into No. 4 capsules to obtain a capsule containing 10 mg of T-5224.

Comparative Example 11

800 mg of T-5224 was dissolved in 40 mL of 0.1 mol / L sodium hydroxide. 4 mL of purified water was added to 4 mL of this solution to obtain a liquid formulation containing 10 mg / mL of T-5224.

Comparative Example 12

800 mg of T-5224 was dissolved in 40 mL of 0.1 mol / L sodium hydroxide. In 4 mL of this solution, 720 mg of hydroxypropylmethylcellulose (TC-5E, manufactured by Shinetsu Kagaku) was dissolved. 4 mL of purified water was added to this solution to obtain a liquid formulation containing 10 mg / mL of T-5224.

Comparative Example 13

800 mg of T-5224 was dissolved in 40 mL of 0.1 mol / L sodium hydroxide. 720 mL of polyethylene glycol 6000 was dissolved in 4 mL of this solution. 4 mL of purified water was added to this solution to obtain a liquid formulation containing 10 mg / mL of T-5224.

Comparative Example 14

10 mg of T-5224 was suspended in 5 mL of purified water to obtain a suspension containing 10 mg of T-5224.

Comparative Example 15

12.7 mg of T-5224 trisodium salt was dissolved in 5 mL of purified water to obtain an aqueous solution containing 10 mg of T-5224.

Comparative Example 16

450 mg of powder filtered through a 60 mesh sieve was filled into No. 000 capsules to obtain a capsule containing 450 mg of T-5224.

Example 1

T-5224 150 mg, polyvinylpyrrolidone K-30 (Plasdone K29 / 32, manufactured by ISP) 450 mg, L-arginine (manufactured by Ajinomoto Corp.) 450 mg, lactose for direct use (Tabletose 80, manufactured by Meggle Corp. ) 1500 mg, 52.5 mg of crospovidone (Kollidon CL, manufactured by BASF Corp.), and 22.5 mg of magnesium stearate were weighed, mixed, sieved through a 30 mesh (sieving interval: 500 µm), and mixed to obtain a tablet powder. Tableting powder 175 mg was compressed into a mortar having a diameter of 8.0 mm to obtain a tablet containing 10 mg of T-5224.

Example 2

T-5224 100 mg, polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) 300 mg, L-arginine (manufactured by Ajinomoto Corp.) 600 mg, β-cyclodextrin (Celldex B-100, Nihon 1000 mg of Shokuhin kako Corp. Ltd., 40 mg of crospovidone (Kollidon CL, BASF Corp.) and 20 mg of magnesium stearate were weighed, mixed, sieved through a 30 mesh sieve, and then mixed into tableting powder. . Tableting powder 206 mg was compressed into a mortar with a diameter of 8.5 mm to obtain a tablet containing 10 mg of T-5224.

Example 3

100 mg of T-5224, polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP) 300 mg, potassium carbonate 600 mg, β-cyclodextrin (Celldex B-100, manufactured by Nihon Shokuhin kako Corp. Ltd.) ) 1000 mg, crospovidone (Kollidon CL, manufactured by BASF Corp.) and 20 mg of magnesium stearate were weighed, mixed, sieved through a 30 mesh sieve, and mixed to obtain a tableting powder. Tableting powder 206 mg was compressed into a mortar with a diameter of 8.5 mm to obtain a tablet containing 10 mg of T-5224.

Example 4

1.2 g of T-5224, polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP) 3.6 g, L-arginine (Ajinomoto Corp.) 7.2 g, direct lactose (Tabletose 80, manufactured by Meggle Corp. ) 3.6 g, crospovidone (Kollidon CL, manufactured by BASF Corp.) and 0.156 g of magnesium stearate were weighed, mixed, filtered through a 30 mesh sieve, and mixed to obtain a tablet powder. Tableting powder 133.9 mg was compressed into a mortar with a diameter of 7.5 mm to obtain a tablet containing 10 mg of T-5224.

Example 5

10 g of T-5224, polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP) 30 g, L-arginine (manufactured by Ajinomoto Corp.) 30 g, direct lactose (Pharmatose DCL-14, DMV Corp.) 61.1 g, carboxymethyl starch sodium (Primogel, manufactured by Matsutani Corp.) 2.6 g, and magnesium stearate 1.3 g were weighed, mixed, sieved through a 30 mesh sieve, and mixed to form a tableting powder. 135 mg of tableting powder was compressed into a mortar with a diameter of 7.0 mm to obtain a tablet containing 10 mg of T-5224.

Example 6

T-5224 1.2 g, polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) 3.6 g, L-arginine (manufactured by Ajinomoto Corp.) 2.4 g, lactose for direct use (Tabletose 80, manufactured by Meggle Corp. ) 8.4 g, crospovidone (Kollidon CL, manufactured by BASF Corp.) and 0.156 g of magnesium stearate were weighed, mixed, sieved through a 30 mesh sieve, and mixed to obtain a tablet powder. Tableting powder 133.9 mg was compressed into a mortar with a diameter of 7.5 mm to obtain a tablet containing 10 mg of T-5224.

Example 7

1.2 g of T-5224, polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) 3.6 g, L-arginine (manufactured by Ajinomoto Corp.) 1.2 g, lactose for direct use (Tabletose 80, manufactured by Meggle Corp. 9.6 g), 0.312 g of collidone CL (manufactured by BASF Corp.) and 0.156 g of magnesium stearate were weighed, mixed, filtered through a 30 mesh sieve, and mixed to obtain a tableting powder. Tableting powder 133.9 mg was compressed into a mortar with a diameter of 7.5 mm to obtain a tablet containing 10 mg of T-5224.

Example 8

20 g of T-5224, 10 g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, manufactured by ISP), humidified, 60 g of L-arginine (manufactured by Ajinomoto Corp.), mannitol for direct use (Parteck M100 Weighed 129.7 g of Merck Corp.), 4.6 g of sodium carboxymethyl starch (Primogel, Matsutani Corp.) and 5.8 g of magnesium stearate, mixed, filtered through a 30 mesh sieve, mixed and tableted It was made into powder. The tableting powder was compressed into mortar having a diameter of 6.5 mm, and then dried at 40 ° C. to obtain a tablet containing 10 mg of T-5224 having a tablet weight of 115 mg.

Example 9

20 g of T-5224, 20 g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, manufactured by ISP), humidified, 60 g of L-arginine (manufactured by Ajinomoto Corp.), mannitol for direct use (Parteck M100 119.6 g of a pulverized product of Merck Corp.), 4.6 g of sodium carboxymethyl starch (Primogel, manufactured by Matsutani Corp.) and 5.8 g of magnesium stearate were weighed, mixed, sieved through a 30 mesh sieve, mixed and tableted. It was made into powder. The tableting powder was compressed into mortar having a diameter of 6.5 mm, and then dried at 40 ° C. to obtain a tablet containing 10 mg of T-5224 having a tablet weight of 115 mg.

Example 10

20 g of T-5224, 60 g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, manufactured by ISP), humidified, 60 g of L-arginine (manufactured by Ajinomoto Corp.), mannitol for direct use (Parteck M100 79.6 g of a pulverized product of Merck Corp.), 4.6 g of sodium carboxymethyl starch (Primogel, manufactured by Matsutani Corp.) and 5.8 g of magnesium stearate were weighed, mixed, sieved through a 30 mesh sieve, mixed and tableted. It was made into powder. The tableting powder was compressed into mortar having a diameter of 6.5 mm, and then dried at 40 ° C. to obtain a tablet containing 10 mg of T-5224 having a tablet weight of 115 mg.

Example 11

10g of T-5224, 3g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company), humidified 30g of L-arginine (manufactured by Ajinomoto Corp.), mannitol for direct use (Parteck M100 , 67.4 g of pulverized product of Merck Corp.), 2.3 g of sodium carboxymethyl starch (Primogel, manufactured by Matsutani Corp.) and 2.3 g of magnesium stearate were weighed, mixed, sieved through a 30 mesh sieve, mixed, and then compressed into tablets. It was made into powder. The tableting powder was compressed into mortar having a diameter of 6.5 mm, and then dried at 40 ° C. to obtain a tablet containing 10 mg of T-5224 having a tablet weight of 115 mg.

Example 12

T-5224 100 mg, polyvinylpyrrolidone K-25 (Plasdone K25, ISP) 300 mg, L-arginine (Ajinomoto Corp.) 600 mg, β-cyclodextrin (Celldex B-100, Nihon Shokuhin kako Corp. Ltd.) 1000 mg, crospovidone (Kollidon CL, BASF Corp.) 40 mg, and magnesium stearate 20 mg were weighed, mixed, filtered through a 30 mesh sieve, and mixed to form a tableting powder. Tableting powder 206 mg was compressed into a mortar with a diameter of 8.5 mm to obtain a tablet containing 10 mg of T-5224.

Example 13

1.2 g of T-5224, polyvinylpyrrolidone K-17 (Kollidon 17PF, manufactured by BASF Corp.), 3.6 g of L-arginine (manufactured by Ajinomoto Corp.), mannitol (parteck M100, manufactured by Merck Corp.) 8.4 g, 0.312 g crospovidone (Kollidon CL, manufactured by BASF Corp.) and 0.156 g of magnesium stearate were weighed, mixed, sieved through a 30 mesh sieve, and mixed to obtain a tablet powder. Tableting powder 133.9 mg was compressed into a mortar with a diameter of 7.5 mm to obtain a tablet containing 10 mg of T-5224.

Example 14

T-5224 1.2 g, polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP) 3.6 g, L-arginine (Ajinomoto Corp.) 3.6 g, direct lactose (Tabletose 80, manufactured by Meggle Corp. ) 3.6 g, β-cyclodextrin (Celldex B-100, manufactured by Nihon Shokuhin kako Corp. Ltd.) 3.6 g, crospovidone (Kollidon CL, manufactured by BASF Corp.), 0.312 g, magnesium stearate 0.156 g, were weighed and mixed , 30 mesh sieve, and mixed to form a tableting powder. Tableting powder 133.9 mg was compressed into a mortar with a diameter of 7.5 mm to obtain a tablet containing 10 mg of T-5224.

Example 15

T-5224 100 mg, polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) 300 mg, L-arginine (Ajinomoto Corp.) 300 mg, β-cyclodextrin (Celldex B-100, Nihon 300 mg of Shokuhin kako Corp. Ltd.), 20 mg of sodium carboxymethyl starch (Primogel, manufactured by Matsutani Corp.) and 10 mg of magnesium stearate were weighed, mixed, filtered through a 30 mesh sieve, and then mixed with a tableting powder. It was set as. 103 mg of tableting powder was compressed into a mortar having a diameter of 6.5 mm to obtain a tablet containing 10 mg of T-5224.

Example 16

5 g of T-5224, 5 g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP), 15 g of L-arginine (manufactured by Ajinomoto Corp.), mannitol (parteck M100, manufactured by Merck Corp.) 1.68 g 0.55 g of sodium carboxymethyl starch (Primogel, manufactured by Matsutani Corp.) and 0.28 g of magnesium stearate were weighed, mixed, filtered through a 30 mesh sieve, and mixed to obtain a mixed powder. The mixed powder was dry granulated to obtain a T-5224 granule.

Example 17

2 g of T-5224, 2 g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP), 6 g L-arginine (manufactured by Ajinomoto Corp.), and mannitol (parteck M100, manufactured by Merck Corp.) for direct use 12.1 g of this, 0.5 g of sodium carboxymethyl starch (Primogel, manufactured by Matsutani Corp.) and 0.5 g of magnesium stearate were weighed, mixed, filtered through a 30 mesh sieve, and mixed to obtain a mixed powder. The mixed powder was filled with 230 mg of No. 2 capsules using a circular capsule charger to obtain a capsule containing 20 mg of T-5224.

Example 18

T-5224 2g, polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP) 2g, L-arginine (Ajinomoto Corp.) 6g, corn starch 12.1g, carboxymethyl starch sodium (Primogel, Matsutani Corp.) 0.5 g and magnesium stearate 0.5 g were weighed, mixed, filtered through a 30 mesh sieve, and mixed to obtain a mixed powder. The mixed powder was filled with 230 mg of No. 2 capsules using a circular capsule charger to obtain a capsule containing 20 mg of T-5224.

Example 19

8 g of T-5224, polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP) 8 g, L-arginine (manufactured by Ajinomoto Corp.) 24 g, sodium carboxymethyl starch (Primogel, Matsutani Corp.) 0.8 g and 0.8 g of magnesium stearate were weighed, mixed, filtered through a 30 mesh sieve, and mixed to obtain a mixed powder. The mixed powder was filled with 416 mg of No. 0 capsule using a circular capsule charger to obtain a capsule containing 80 mg of T-5224.

Example 20

4 g of T-5224, 4 g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, manufactured by ISP), 12 g of L-arginine (manufactured by Ajinomoto Corp.), and mannitol (parteck M100, manufactured by Merck Corp.) for direct use 24.2 g of one, 0.9 g of sodium carboxymethyl starch (Primogel, manufactured by Matsutani Corp.) and 0.9 g of magnesium stearate were weighed, mixed, sieved through a 30 mesh sieve, and mixed to obtain a mixed powder. 460 mg of the mixed powder was filled into No. 0 capsules using a circular capsule charger to obtain a capsule containing 40 mg of T-5224.

Example 21

1g of T-5224, 1g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, manufactured by ISP), humidified, 3g of L-arginine (manufactured by Ajinomoto Corp.), sodium carboxymethyl starch ( 0.1 g of Primogel, manufactured by Matsutani Corp., and 0.1 g of magnesium stearate were weighed, mixed, filtered through a 30 mesh sieve, and mixed to form a tableting powder. The tableting powder was compressed into mortars having a diameter of 10 mm and then dried at 40 ° C. to obtain tablets containing 80 mg of T-5224 having a tablet weight of 416 mg.

Example 22

10g of T-5224, 10g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company), humidified 30g of L-arginine (manufactured by Ajinomoto Corp.), sodium carboxymethyl starch ( 1 g of Primogel, manufactured by Matsutani Corp., and 1 g of magnesium stearate were weighed, mixed, sieved through a 30 mesh sieve, and mixed to obtain a tableting powder. The tableting powder was compressed into a mortar having a diameter of 8.5 mm, and then dried at 40 ° C. to obtain a tablet containing 40 mg of T-5224 having a tablet weight of 208 mg.

Example 23

106 mg of T-5224 ammonium salt, polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) 300 mg, L-arginine (Ajinomoto Corp.) 300 mg, direct lactose (Tabletose 80, Meggle Corp. 1000 mg), 40 mg crospovidone (manufactured by Kollidon CL, BASF Corp.) and 20 mg magnesium stearate were weighed, mixed, filtered through a 30 mesh sieve, and mixed to obtain a tablet powder. 176.6 mg of tableting powder was compressed into a mortar having a diameter of 8 mm to obtain a tablet of T-5224 ammonium salt (containing 10 mg of T-5224).

Example 24

1 g of T-5224, polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP) 3 g, L-arginine (manufactured by Ajinomoto Corp.) 10 g, hydroxypropyl-β-cyclodextrin (Celldex HP-β- CD, 10 g of Nihon Shokuhin kako Corp. Ltd.), 0.48 g of crospovidone (Kollidon CL, BASF Corp.), 0.24 g of magnesium stearate, weighed, mixed, sieved, and mixed with a tableting powder It was set as. 247.2 mg of tableting powder was compressed into a mortar with a diameter of 8.5 mm to obtain a tablet containing 10 mg of T-5224.

Example 25

Humidified 50 g of T-5224, 50 g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, manufactured by ISP), humidified 150 g of L-arginine (manufactured by Ajinomoto Corp.), mannitol for direct use (Parteck M100 , Merck Corp.), 302 g, sodium carboxymethyl starch sodium (Primogel, Matsutani Corp.) 11.5 g, magnesium stearate 11.5 g were weighed, mixed, filtered through a 30 mesh sieve, mixed and tableted It was made into powder. The tableting powder was compressed into mortar with a diameter of 8.5 mm, and then dried at 40 ° C. to obtain a tablet containing 20 mg of T-5224 having a tablet weight of 230 mg.

Example 26

20 g of T-5224, polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) 21.5 g, L-arginine (Ajinomoto Corp.) humidification product 73.0 g, direct mannitol (Parteck M100, Merck Corp. 121.5 g of ground products, 4.7 g of carboxymethyl starch sodium (Primogel, manufactured by Matsutani Corp.) and 4.6 g of magnesium stearate were weighed, mixed, sieved through a 30 mesh sieve, and mixed to obtain a tablet powder. The tableting powder was compressed into a mortar having a diameter of 8.5 mm and then dried at 50 ° C. to obtain a tablet containing 20 mg of T-5224 having a tablet weight of 230 mg.

Example 27

800 mg of T-5224 was dissolved in 40 mL of 0.1 mol / L sodium hydroxide. After dissolving 240 mg of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) in 4 mL of this solution, 4 mL of purified water was added to obtain a liquid formulation containing 10 mg / mL of T-5224.

Example 28

800 mg of T-5224 was dissolved in 40 mL of 0.1 mol / L sodium hydroxide. After dissolving 480 mg of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) in 4 mL of this solution, 4 mL of purified water was added to obtain a liquid formulation containing 10 mg / mL of T-5224.

Example 29

800 mg of T-5224 was dissolved in 40 mL of 0.1 mol / L sodium hydroxide. After dissolving 720 mg of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) in 4 mL of this solution, 4 mL of purified water was added to obtain a liquid formulation containing 10 mg / mL of T-5224.

Example 30

160 mg of T-5224 was dissolved in 8 mL of 0.1 mol / L sodium hydroxide. After dissolving 480 mg of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) in this solution, 8 mL of 0.1 mol / L hydrochloric acid was added to give 10 mg / mL of T-5224 having a pH of 3.5. The contained liquid formulation was obtained.

Example 31

160 mg of T-5224 was dissolved in 8 mL of 0.1 mol / L sodium hydroxide. After dissolving 480 mg of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) in this solution, 8 mL of 0.1 mol / L tartaric acid was added to give 10 mg / mL of T-5224 having a pH of 3.2. The contained liquid formulation was obtained.

Example 32

160 mg of T-5224 was dissolved in 8 mL of 0.1 mol / L sodium hydroxide. After dissolving 480 mg of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) in this solution, 5 mL of purified water was added to 5 mL of this solution, and 10 mg / mL of T-5224 having a pH of 10.8. The contained liquid formulation was obtained.

Example 33

160 mg of T-5224 was dissolved in 8 mL of 10 mg / mL L-arginine aqueous solution. After dissolving 480 mg of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) in this solution, 8 mL of 0.1 mol / L hydrochloric acid was added to give 10 mg / mL of T-5224 having a pH of 5.2. The contained liquid formulation was obtained.

Example 34

160 mg of T-5224 was dissolved in 8 mL of 10 mg / mL L-arginine aqueous solution. After dissolving 480 mg of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, manufactured by ISP) in this solution, 8 mL of 0.1 mol / L tartaric acid was added again to give 10 mg / T of T-5224 of pH3.3. A solution containing mL was obtained.

Example 35

160 mg of T-5224 was dissolved in 8 mL of 20 mg / mL L-arginine aqueous solution. After dissolving 480 mg of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) in this solution, 8 mL of purified water was added to the solution containing 10 mg / mL of T-5224 at pH8.8. Got it.

Example 36

1 g of T-5224 was dissolved in 50 mL of 0.1 mol / L sodium hydroxide. After dissolving 3 g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP) in this solution, 50 mL of purified water was added to obtain a liquid formulation containing 10 mg / mL of T-5224 having a pH of 10.8. .

Example 37

1 g of T-5224 was dissolved in 50 mL of 0.1 mol / L sodium hydroxide. After dissolving 3 g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP) in this solution, 27 mL of 0.3 mol / L hydrochloric acid solution and 23 mL of purified water were added to the solution to give a T- of pH 1.6. A liquid formulation containing 5224 of 10 mg / mL was obtained.

Example 38

2 g of T-5224 was dissolved in 15.5 mL of 0.5 mol / L sodium hydroxide and 3.5 mL of purified water. Purified water was added to 10 mL of this solution to make 100 mL, and purified water was further added to 10 mL of this solution to make 100 mL. 90 mg of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) was dissolved in 30 mL of this solution to obtain a solution containing 1 mg / mL of T-5224 having a pH of 7.5.

Example 39

2 g of T-5224 was dissolved in 15.5 mL of 0.5 mol / L sodium hydroxide and 3.5 mL of purified water. Purified water was added to 10 mL of this solution to make 100 mL, and purified water was further added to 10 mL of this solution to make 100 mL. Again, purified water was added to 10 mL of this solution to make 100 mL. 30 mg of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) was dissolved in this solution to obtain a solution containing 0.1 mg / mL of T-5224 having a pH of 7.0.

Example 40

1 g of T-5224 was dissolved in 43 mL of 0.1 mol / L sodium hydroxide. 3 g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP) was dissolved in this solution. 2.5 mL of 1 mol / L hydrochloric acid was added to this solution to obtain a liquid formulation containing 20 mg / mL of T-5224 at pH5.9.

Example 41

0.5 g of T-5224 was dissolved in 3.9 mL of 0.5 mol / L sodium hydroxide and 5.1 mL of purified water. 1.5g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) was dissolved in this solution, and the liquid formulation containing 50 mg / mL of T-5224 of pH8.3 was obtained.

Example 42

0.5 g of T-5224 and 0.5 g of L-arginine were dissolved in 9 mL of purified water. 1.5g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP) was dissolved in this solution. 0.8 mL of 1 mol / L hydrochloric acid solution was added to this solution to obtain a solution containing 50 mg / mL of T-5224 at pH 7.8.

Example 43

1 g of T-5224 was dissolved in 7.7 mL of 0.5 mol / L sodium hydroxide and 10 mL of purified water. 0.5g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) was dissolved in this solution, and the liquid formulation containing 50 mg / mL of T-5224 of pH9.3 was obtained.

Example 44

1 g of T-5224 was dissolved in 7.7 mL of 0.5 mol / L sodium hydroxide and 10 mL of purified water. 1g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) was dissolved in this solution, and the liquid formulation containing 50 mg / mL of T-5224 of pH9.0 was obtained.

Example 45

1 g of T-5224 was dissolved in 7.7 mL of 0.5 mol / L sodium hydroxide and 10 mL of purified water. 1.5g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) was dissolved in this solution, and the liquid formulation containing 50 mg / mL of T-5224 of pH8.7 was obtained.

Example 46

1 g of T-5224 was dissolved in 7.7 mL of 0.5 mol / L sodium hydroxide and 10 mL of purified water. 2g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) was melt | dissolved in this solution, and the liquid formulation containing 50 mg / mL of T-5224 of pH8.4 was obtained.

Example 47

1 g of T-5224 was dissolved in 7.7 mL of 0.5 mol / L sodium hydroxide and 10 mL of purified water. 3g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) was dissolved in this solution, and the liquid formulation containing 50 mg / mL of T-5224 of pH8.1 was obtained.

Example 48

2 g of T-5224 was dissolved in 15.5 mL of 0.5 mol / L sodium hydroxide. 2g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) was dissolved in this solution, and the liquid formulation containing 100 mg / mL of T-5224 of pH9.6 was obtained.

Example 49

2 g of T-5224 was dissolved in 15.5 mL of 0.5 mol / L sodium hydroxide. 4g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) was melt | dissolved in this solution, and the liquid formulation containing 100 mg / mL of T-5224 of pH8.8 was obtained.

Example 50

2 g of T-5224 was dissolved in 7.7 mL of 1 mol / L sodium hydroxide. 1g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) was dissolved in this solution, and the liquid formulation containing 200 mg / mL of T-5224 of pH10.0 was obtained.

Example 51

2 g of T-5224 was dissolved in 7.7 mL of 1 mol / L sodium hydroxide. 2g of polyvinylpyrrolidone K-30 (Plasdone K29 / 32, ISP company) was melt | dissolved in this solution, and the liquid formulation containing 200 mg / mL of T-5224 of pH9.4 was obtained.

The T-5224 oral composition containing the polyvinylpyrrolidone of the present invention does not require any new manufacturing equipment, is manufactured by a simple process, and stably maintains dissolution even by changing pH in the digestive tract. It is also useful as an oral pharmaceutical composition that improves the absorption of the digestive tract.

Claims (11)

3- {5- [4- (cyclopentyloxy) -2-hydroxybenzoyl] -2-[(3-hydroxy-1,2-benzisoxazol-6-yl) methoxy] phenyl} propionic acid or its An oral composition comprising a salt and polyvinylpyrrolidone. 3- {5- [4- (cyclopentyloxy) -2-hydroxybenzoyl] -2-[(3-hydroxy-1,2-benzisoxazol-6-yl) methoxy] phenyl} propionic acid or its An oral solid composition, wherein the salt, polyvinylpyrrolidone, and 5 W / V% aqueous solution contain a basic substance having a pH of 10 or higher. The method of claim 2, An oral solid composition, wherein the basic substance in which the 5W / V% aqueous solution exhibits a pH of 10 or more is L-arginine or potassium carbonate. The method of claim 2, Oral solid composition characterized by the basic material whose 5W / V% aqueous solution shows pH10 or more is L-arginine. The method according to claim 2, wherein An oral solid composition comprising a water-soluble excipient. The method according to claim 2, wherein Oral solid composition, characterized in that the tablet or capsule. The method according to claim 2, wherein Oral solid composition, characterized in that the tablet. 3- {5- [4- (cyclopentyloxy) -2-hydroxybenzoyl] -2-[(3-hydroxy-1,2-benzisoxazol-6-yl) methoxy] phenyl} propionic acid or its An oral aqueous liquid preparation containing a salt and polyvinylpyrrolidone. The method of claim 8, Concentration of 3- {5- [4- (cyclopentyloxy) -2-hydroxybenzoyl] -2-[(3-hydroxy-1,2-benzisoxazol-6-yl) methoxy] phenyl} propionic acid Oral aqueous solution is characterized in that the 0.01 ~ 20W / V%. The method according to claim 8 and 9, Polyvinylpyrrolidone is 3- {5- [4- (cyclopentyloxy) -2-hydroxybenzoyl] -2-[(3-hydroxy-1,2-benzisoxazol-6-yl) meth It is 1-10 times with respect to oxy] phenyl} propionic acid, The aqueous oral liquid agent characterized by the above-mentioned. The method according to claim 8, wherein Aqueous oral aqueous solution, characterized in that the pH of the oral aqueous solution is 3-9.